The Menstrual Cycle and Reproductive Hormones
Spec mapping: AQA 7402 Section 3.6.4 — hormonal control of the menstrual cycle, with reference to FSH, LH, oestrogen and progesterone interactions, positive and negative feedback loops, and applied coverage of contraception and assisted reproduction (refer to the official AQA specification document for exact wording).
The human menstrual cycle is the most architecturally sophisticated example of hormonal coordination on the AQA A-Level syllabus. Over approximately 28 days, four hormones — follicle-stimulating hormone (FSH), luteinising hormone (LH), oestrogen and progesterone — choreograph the maturation of a follicle, the release of an ovum, the preparation of the uterine endometrium, and either pregnancy support or menstruation. The cycle showcases every feedback motif developed in lesson 0: sustained negative feedback (during the early follicular and the luteal phases), positive feedback (the LH surge at ovulation), set-point resetting (the luteal-phase progesterone rise blunts FSH and LH), and antagonistic hormone pairs (oestrogen with progesterone, FSH with inhibin). It also showcases the steroid-vs-peptide distinction developed in lesson 4: FSH and LH are anterior-pituitary peptide hormones acting via cell-surface receptors and cAMP cascades; oestrogen and progesterone are gonadal steroid hormones acting via intracellular receptors and transcription factors. The cycle is therefore the consolidating worked example for everything else in this course.
Key Definition: The menstrual cycle is the recurring ~28-day hormonal and physiological cycle in non-pregnant women of reproductive age, characterised by maturation of an ovarian follicle, ovulation, formation of a corpus luteum, and either implantation of a fertilised ovum or shedding of the uterine endometrium as menstrual flow.
The Four-Phase Architecture
The cycle is divided into phases by the ovarian and endometrial events that mark them. Day 1 is conventionally the first day of menstrual flow.
1. Menstrual phase (~days 1–5)
- Ovarian event: a new cohort of antral follicles begins to develop in response to rising FSH.
- Endometrial event: the previous cycle's endometrium (built up but unused) is shed as menstrual flow — vasoconstriction of spiral arteries triggered by falling progesterone causes endometrial ischaemia, necrosis and detachment.
- Hormones: all four hormones at near-basal levels. FSH has just begun to rise.
2. Follicular (proliferative) phase (~days 5–13)
- Ovarian event: one follicle (the "dominant follicle") emerges from the cohort, outgrowing the others. The selected follicle is maximally sensitive to FSH and produces increasing amounts of oestrogen as it grows.
- Endometrial event: oestrogen drives endometrial proliferation — the lining thickens from ~1 mm to ~10 mm through cell division and angiogenesis. New blood vessels supply the thickening tissue.
- Hormones: FSH initially rises, then falls as oestrogen and inhibin (a peptide hormone from granulosa cells) suppress FSH by negative feedback at the pituitary. Oestrogen rises sharply, reaching its first peak just before ovulation. LH stays low until the surge.
3. Ovulation (~day 14)
- Ovarian event: the mature follicle ruptures; the secondary oocyte and surrounding cumulus cells are released into the peritoneal cavity and swept into the fallopian tube by fimbriae.
- Endometrial event: endometrial proliferation is complete; the lining is structurally ready for implantation.
- Hormones: the LH surge — a sudden, transient spike of LH (and FSH) driven by positive feedback. Oestrogen, having risen past a threshold (~200 pg mL⁻¹) and remained above it for ~36–48 hours, switches its action at the hypothalamus from inhibitory to stimulatory, driving GnRH release that triggers a massive LH surge from the anterior pituitary. The LH surge triggers ovulation ~24 hours later.
4. Luteal phase (~days 14–28)
- Ovarian event: the ruptured follicle reorganises into the corpus luteum ("yellow body"), a temporary endocrine structure that secretes progesterone and oestrogen.
- Endometrial event: progesterone transforms the proliferative endometrium into a secretory endometrium — the glands begin secreting glycogen-rich uterine milk, the stroma becomes oedematous and vascular, ready for implantation.
- Hormones: progesterone rises sharply and dominates. Oestrogen rises secondarily. Inhibin and progesterone both suppress FSH and LH (negative feedback). If fertilisation does not occur, the corpus luteum regresses after ~10 days; progesterone and oestrogen fall; menstruation begins; FSH is no longer suppressed and rises — initiating the next cycle.
The Four Hormones — A Closer Look
Follicle-stimulating hormone (FSH)
- Source: anterior pituitary gonadotrophs.
- Chemistry: glycoprotein (peptide hormone) — water-soluble, cell-surface receptor, cAMP cascade.
- Target: granulosa cells of the developing follicle. FSH receptor is a Gαₛ-coupled GPCR → adenylyl cyclase → cAMP → PKA (the canonical cascade developed in lesson 4).
- Action: stimulates follicle growth, aromatase expression (converting androgens into oestrogen), and inhibin secretion.
- Regulation: secretion driven by hypothalamic GnRH; suppressed by oestrogen and inhibin in negative feedback.
Luteinising hormone (LH)
- Source: anterior pituitary gonadotrophs (the same cells secrete both FSH and LH, in distinct proportions).
- Chemistry: glycoprotein peptide hormone.
- Target: theca cells of the developing follicle (producing androgen substrate for granulosa aromatase) and, after ovulation, the corpus luteum.
- Action: drives androgen synthesis in theca cells (pre-ovulation); triggers ovulation (the LH surge); sustains the corpus luteum (luteal phase).
- Regulation: GnRH from hypothalamus; positive feedback from high oestrogen at mid-cycle (the surge); negative feedback from progesterone and moderate oestrogen at other times.
Oestrogen (oestradiol)
- Source: granulosa cells of follicle (follicular phase); corpus luteum (luteal phase); placenta (in pregnancy).
- Chemistry: steroid hormone — lipid-soluble, intracellular receptor (ERα, ERβ), transcription factor.
- Target: many tissues — endometrium (proliferation), breast (development), hypothalamus and pituitary (feedback), bone (preservation), liver (lipid metabolism).
- Action: endometrial proliferation; bone protection; the dual feedback (negative at low concentrations and short durations; positive at high concentrations sustained for ~36 hours, producing the LH surge).
- Regulation: synthesised under FSH (and LH-driven androgen) stimulation; clearance via hepatic metabolism.
Progesterone
- Source: corpus luteum (luteal phase); placenta (in pregnancy).
- Chemistry: steroid hormone — lipid-soluble, intracellular receptor.
- Target: endometrium (secretory transformation), breast (preparation for lactation), hypothalamus and pituitary (negative feedback), smooth muscle of uterus (suppression of contractility — preserving pregnancy).
- Action: secretory endometrium; pregnancy maintenance; basal-body-temperature rise of ~0.3–0.5 °C (resetting hypothalamic thermoregulatory set point — synoptic with lesson 0).
- Regulation: synthesised under LH stimulation; clearance via hepatic metabolism.
The Hormonal Choreography Visualised
flowchart LR
H[Hypothalamus<br/>GnRH] --> P[Anterior pituitary]
P --> FSH[FSH]
P --> LH[LH]
FSH --> F[Follicle<br/>granulosa cells]
LH --> F2[Follicle<br/>theca cells]
F --> E[Oestrogen]
F2 --> E
E -.->|negative feedback<br/>most of cycle| H
E -.->|negative feedback| P
E -.->|positive feedback<br/>mid-cycle peak| H
LH --> CL[Corpus luteum]
CL --> Prog[Progesterone]
Prog -.->|negative feedback| H
Prog -.->|negative feedback| P
E --> En[Endometrium<br/>proliferation]
Prog --> En2[Endometrium<br/>secretion]
Feedback Loops — Negative and Positive
Negative feedback (most of the cycle)
In the early follicular and the luteal phases, oestrogen, progesterone and inhibin suppress FSH and LH at both the hypothalamus and the anterior pituitary. The loop is stabilising — it prevents excessive gonadotropin secretion and keeps the cycle within bounds. The loop architecture is exactly as developed in lesson 0: deviation → receptor → coordinator → effector → response → deviation reduced.
Positive feedback (the LH surge)
Just before ovulation, oestrogen exceeds a threshold (~200 pg mL⁻¹) and remains there for ~36 hours. The hypothalamic response to oestrogen switches from inhibitory to stimulatory — GnRH pulse frequency rises sharply, driving a massive LH (and smaller FSH) surge from the pituitary. The surge is the trigger for ovulation. Positive feedback is rare and transient (lesson 0) — it terminates once ovulation occurs and oestrogen begins to fall.
The switch between negative and positive feedback at a single hormone (oestrogen, depending on concentration and duration) is among the most architecturally elegant features of mammalian physiology. The mechanism involves kisspeptin neurones in the hypothalamus, which are GnRH-pulse-generators with bimodal oestrogen sensitivity.
Feedback in pregnancy
If fertilisation occurs, the embryo implants ~6–8 days after ovulation. The implanted blastocyst secretes human chorionic gonadotropin (hCG) — a peptide hormone similar in structure to LH. hCG rescues the corpus luteum, preventing its regression and maintaining progesterone secretion through the first trimester. By ~10 weeks, the placenta itself takes over progesterone secretion, and the corpus luteum regresses. Throughout pregnancy, high progesterone suppresses FSH and LH — there is no follicle development and no ovulation. Pregnancy is therefore a sustained negative-feedback state.
Menopause
Menopause is the cessation of menstrual cyclicity, typically around age 50, marking the end of natural fertility. The proximate cause is exhaustion of the follicle reserve. A woman is born with ~1–2 million primordial follicles; by puberty ~400 000 remain; ~400 develop to ovulation across a reproductive lifetime; the rest undergo atresia. When few follicles remain, oestrogen and inhibin production falls; the hypothalamic-pituitary axis loses its negative-feedback brake; FSH and LH rise (sometimes 10–20-fold). Periods become irregular, then stop. The hormonal sequelae — hot flushes (vasomotor instability from altered hypothalamic set points), bone density loss (oestrogen-protective effect on bone removed), cardiovascular risk shift, mood changes — are the consequences of the new hormonal milieu.
Hormone replacement therapy (HRT) replaces oestrogen (with or without progesterone) to mitigate symptoms; the risk–benefit profile has been the subject of considerable clinical research.
Hormonal Contraception
The combined oral contraceptive pill (COCP) provides the textbook applied example. The pill contains synthetic oestrogen (typically ethinylestradiol) and a synthetic progestin (varying chemistry across formulations). The mechanism exploits the cycle's own negative-feedback architecture:
- Suppression of FSH and LH: sustained oestrogen and progestin in plasma exert continuous negative feedback at the hypothalamus and pituitary. GnRH pulses are blunted; FSH and LH stay low; no follicle develops to ovulation, no LH surge occurs.
- Cervical mucus thickening: progestin makes cervical mucus thick and hostile to sperm.
- Endometrial modification: progestin alters endometrial development, reducing receptivity to implantation should ovulation somehow occur.
- Withdrawal bleed: typical regimens give 21 days of active pill followed by 7 placebo days. The hormone-free interval allows oestrogen and progestin to fall; the endometrium sheds (a withdrawal bleed mimicking menstruation but pharmacologically driven).
Progestin-only pills, implants and injectables omit oestrogen, relying on cervical mucus thickening and partial ovulation suppression. They have different side-effect profiles and are used when oestrogen is contraindicated.
Assisted Reproduction — IVF
In vitro fertilisation (IVF) is the canonical reproductive-medicine application of the cycle. The protocol manipulates the hormonal axis to recover multiple mature oocytes per cycle:
- Pituitary suppression: a GnRH agonist or antagonist is given, suppressing endogenous FSH and LH.
- Controlled ovarian stimulation: high-dose recombinant FSH is injected for ~10 days, driving multiple follicles (rather than a single dominant follicle) to maturity.
- Ovulation trigger: a single injection of hCG (which mimics the LH surge) triggers final oocyte maturation.
- Oocyte retrieval: ~36 hours later, oocytes are aspirated transvaginally under ultrasound guidance.
- Fertilisation in vitro: oocytes are combined with sperm in culture; or, in intracytoplasmic sperm injection (ICSI), a single sperm is injected into each oocyte.
- Embryo culture: fertilised oocytes are cultured for 3–5 days, reaching the cleavage or blastocyst stage.
- Embryo transfer: one (or occasionally more) embryo is transferred to the uterus; the woman receives progesterone supplementation to support the endometrium.
- Pregnancy test: ~10–14 days later. Success rates per cycle ~25–40% in good prognosis cases, lower with advanced maternal age.
Fertility drugs such as clomiphene citrate act as selective oestrogen receptor modulators (SERMs) — they antagonise oestrogen receptors at the hypothalamus, blocking negative feedback, so the hypothalamus perceives "low oestrogen" and increases GnRH and FSH output. The resulting elevated FSH drives follicle development. Clomiphene is the first-line treatment for anovulatory infertility.
Ethical Considerations (Balanced)
IVF and reproductive technologies raise ethical questions that A-Level candidates should treat carefully and even-handedly:
- Embryo creation and selection: IVF typically produces more embryos than transferred. Surplus embryos are frozen, donated, or destroyed — with varying ethical positions on the moral status of early embryos.
- Pre-implantation genetic testing (PGT): screens embryos for chromosomal abnormalities or specific gene mutations, allowing selective transfer. Some welcome PGT as preventing serious disease; others raise concerns about "designer babies" or social acceptance of disability.
- Sex selection: technically feasible via PGT, legally restricted in many countries to medical indications.
- Access and equity: IVF is expensive; access varies by health system and insurance, raising distributive-justice questions.
- Multiple pregnancies: historically high-order multiples (triplets, quads) carried significant maternal–fetal risk; modern practice transfers single embryos to reduce this.
A balanced exam answer presents the relevant considerations without advocacy.
Common Errors and Mark-Loss Patterns
- Stating that "the LH surge causes the follicle to grow". The LH surge causes the mature follicle to rupture (ovulation). Follicle growth is driven by FSH over the preceding ~14 days.
- Reversing oestrogen and progesterone roles. Oestrogen drives proliferation; progesterone drives secretory transformation. Mnemonic: O for "Oestrogen / Outer-layer building"; P for "Progesterone / Preparing for pregnancy".
- Treating positive feedback as the norm. Positive feedback is rare — it operates briefly at mid-cycle to trigger the LH surge, then terminates.
- Stating that progesterone "causes ovulation". Progesterone rises after ovulation, secreted by the corpus luteum. The LH surge causes ovulation; progesterone follows.
- Forgetting that hCG rescues the corpus luteum if pregnancy occurs. Without hCG (no pregnancy), corpus luteum regresses ~10 days post-ovulation.
- Claiming that the COCP "kills follicles". The pill suppresses FSH and LH so follicles do not develop in the first place. Follicles are not killed; their development is prevented.
- Treating clomiphene as a "hormone". Clomiphene is a SERM — a synthetic small molecule that antagonises oestrogen receptors at the hypothalamus, fooling the negative-feedback loop.
A-Level-Depth Misconceptions